One of the most important paradigm shifts associated with the growth of modern neuroscience in late 20th century is the realization of the extent to which dynamic changes in brain function are the norm rather than the exception. These changes are collectively referred to as examples of "neuroplasticity" and refer to the fact that experiences of various sorts can lead to enduring changes in the structure and functioning of the adult nervous system. Understanding how such brain changes are regulated and what exactly changes is essential for a full elucidation of neural functioning. Such data are also important to provide a scientific underpinning for clinical brain interventions. In many species, the brain changes regularly in response to environmental stimuli such as those that regulate the timing of seasonal reproduction. These changes regulate behavioral and physiological adaptations required for temperate zone species to survive and reproduce successfully in different seasons. Seasonal variation in the brain of songbirds (e.g., canaries Serinus canaria) has emerged as one of the best model systems for the study of naturally occurring hormone-regulated brain plasticity. The volume of brain nuclei associated with the control of vocalizations changes with season in male songbirds. Testosterone (T) promotes the growth of neuronal processes in the spring. Adult neurogenesis occurs in the songbird brain and one way that T promotes increases in brain volume is via neuronal recruitment and survival in these brain areas. Social stimuli, such as the presence of a female, as well as song activity of an individual male can also induce changes in brain morphology independently of testosterone. Ten experiments organized into 5 aims are proposed to study how T and other events that act independently of T can promote this adult neuroplasticity. In aim I studies are proposed to characterize the timing of changes in brain plasticity in relation to changes in endocrine condition associated with changes in seasonal state and to investigate whether there are changes in the brain responsiveness to T action as a function of seasonal reproductive state. In Aim II studies of environmental cues and behavioral events known to facilitate adult neuroplasticity independently of T will be systematically investigated in relation to cellular events associated with variation in song nucleus volume. In particular social cues as well as variation in song production by a male will be manipulated and measures of cell numbers and fibers expressing enzymes related to catecholamine synthesis in the song nuclei will be assessed. In aim III an experiment is proposed to investigate possible male/female differences in the action of T on adult neuroplasticity. In Aim IV the effects of noradrenergic denervation via a specific neurotoxin on T- dependent and independent regulation of brain plasticity will be investigated. We will compare the effects of such a denervation on the ability of T, social cues and singing activity to promote adult seasonal neuroplasticity. Aim V focuses on the regulation of and role played by doublecortin a protein involved in cell migration in adult neuroplasticity. PUBLIC HEALTH RELEVANCE: The elucidation of how morphological and physiological changes in the adult brain are regulated by steroid hormone action and environmental stimuli can provide a scientific underpinning for clinical interventions aimed at relieving behavioral deficits related to brain lesions or degenerative disorders. The studies proposed here concern the regulation of genes related to adult brain change by steroid hormones as well as by social, activity-dependent and environmental stimuli. The genes whose regulation will be studied can influence adult neurogenesis via actions on the processes of cell migration and cell recruitment into neural circuits.